2-sulfamoylbenzoic acid esters



Z-SULFAMOYLBENZOIC ACID ESTERS Glenn *H. Humor, University Park, LosAng'eles 7, N Drawing. Filed Mar. 11, 1959, Ser. No. 798,582

1 Claims. c1. 260 470) Formula I when R; and R represent hydrogen orlower alkyl groups having Ho 6 carbon atoms and R represents a branchedalkyl group having 3 to 6carbon atoms, a cycloalkyl group having 4 to6carbon atoms or an unsaturatedalkyl grouph'aving 3 to 6 carbon atoms.

,Advantageous compounds of thisinvention are repre-- sented by thefollowing structural formula:

Formula II S QeNHa -C O 0 R:

when R represents a branched alkyl group having, 3 to 6 carbon atoms. I

A particularly advantageous and preferred compound of this invention isisopropyl 2-sulfamoylbenzoate which possesses superior muscle relaxantactivity with a minimum of side efiiects.

Surprisingly the compounds of this invention have been iound to have ahigher order of muscle relaxant and anticonvulsant activity than theclosest compounds of the prior art. For instance, the prior art compoundmost closely related structurally to the Z-sulfainoylbenzoatederivatives of this invention is ethyl 2 sulfamoy'lbenz'oatewhosestructure is represented by Formula I when R; and R are hydrogenand R is ethyl iE. Shrader, I.

v Prakt. Chem., 95, 312-26 (1917); abstract, J. Chem.

Soc, 112, I, 709-710 (1917)]. The Shrader reference does not discloseany pharmacodynamic activity for this ethyl ester. The compounds of thisinvention have been unexpectedly found to have a significant level ofmuscle relaxant activity with a low level ofside effects while the priorart compound is much less active. For instance, in a standard test formuscle relaxant activity, namely protection against strychnineconvulsions in mice, the ED for the. ethyl ester of the prior artcompound is 99 rug/kg. While the ED forthe compound of thisinventionmost closely related structurally, namely the i sois indeedsurprising and unexpected.

propyl ester, is SOmgd/kg, at least twice as'a'ctive;

" nited States Patent Patented July 26, 1960 2 'Ihecompounds ofinvention are prepared according to the following synthetic procedures:

' lroee'dure '1 Procedure 3 According to Procedure 1 which isparticularly useful for pre aring Branched alkyI esters ofN-u'nsubstituted nlfemeylbenzoic acid, fsaccharin is treated with aner:- e'ess or "the appropriate alcohol in the presence of a mineral acidsuch as hydrochloric or sulfuric acid. The reaction mixture is, heatedat from about 60 C. to the reflux temper ture of' the alcohol for aperiod of about 16 to about 72 ho rs. Filterin the reaction mixture,concentrating the filtrate, dissolving the residue in organic solventsuch as ethyl acetate or ether, washing the organic solution with adilute aqueous alkaline solution such as sodium or potassium bicarbonatesolution and with water, drying'with a drying agent such as anhydrousinagnes'ium sulfate, filtering and concentrating in vacuo gives a solidmaterial which is' conveniently re crystallized from aqueous alcoholsuch as methanol oiisopropanol to give the compounds of this invention.7

According to. Procedure 2 which is particularly ad= vant'a'geous in thepreparation of compounds in which the esterg'roup is unsaturated and/orthe sulfamoyl group has one or two alkyl substituents, 2-sulfobenzoicanhy= dride (or acidlis converted to its dichloride by treat= ment withan excess of a clilorinating agent such as phosphorus trichlor ide,thionyl chloride or, preferably, phos phorus pentaehloride. veniently atreflux temperature for about two to aboutsix hours. crude2-chlorosulfonylbenzoyl chloride as the residue: This dichlorideis'heated with an excess of the appro priate alcohol at about '40 toabout 55C. for about 16 to about 32 hours. 'Ihe,exces s alcohol isremoved in acid 'eatment orthis 2 -chlorosulfonyl compound in an organicsolvents'uchas ether or benzenew'ith a geese v 6f Oi Hi1 alkylamine andallflwing the mixture- The reactants are heated, con- 7 The reactionmixture is concentrated leaving" 7 to stand for about 24 to about 48hours yields, upon filtration and concentration of the mixture, the2-sulfamoylbenzoates of this invention.

9 According to Procedure 3 whichis'a particularly advantageous procedurefor the preparation of cycloakyl esters of 2-sulfamylbenzoic acid inwhich the sulfamyl group may optionally have alkyl substituents,2-sulfobenzoic anhydride is treated with an excess of the appropriatealcohol at about 35 to about 50 C; for approximately 4 to 8 hours.Removal of the excess alcohol in vacuo leaves, as the residue, the2-sulfobenzoate which -is treated With a chlorinating agent such asphosphorus trichloride, thionyl chloride or, preferably, phosphoruspentachloride. The reactants are heated, conveniently at refluxtemperature, for about two to about four hours Concentration of thereaction mixture gives, as. the residue, the-ester of 2-chlorosulr'onylbenzoate which is treated with an excess'of ammonia or analkylamine in an organic solvent such as ether or benzene. The reactionmixture is allowed to stand for'about 24 to about 48 hours, then workedup, conveniently, by filtering and concentrating the filtrate to givethe 2-sulfamoylbenzoate of this invention.

The following examples are not limiting but are illustrative ofcompounds of this invention and will serve to makefully apparent all thecompounds embraced by the general formula given above.

Example 1 A suspension of 45.8 g. of saccharin in,200 of isopropanolimmersed in an ice bath is saturated with hydrogen chloride. The mixture'is heated in afpres'sure bottle at 70 C. for three days, then filtered.The'filtrate is concentrated in vacuo and the residue is dissolved inethyl acetate and washed with 5% aqueous sodium bicarbonate and withwater. The solution is dried over anhydrous magnesium sulfate, filteredand concentrated in vacuo to give a white solid which is recrystallizedfrom aqueous methanol to give isopropyl 2-sulfamoylbenzoate, M.P., 7275C.

Example 2 A mixture of g. of saccharin, 20 drops of concen- 4 7.0 g. ofdimethylamine in other solution. The resulting mixture is allowed tostandfor 36 hours, then filtered. The excess dimethylamine is removed invacuo. The ethereal residue is washed with water, dried and stripped ofsolvent to give isopropyl 2-(N,N-dimethylsulfamoyl) benzoate, an orangeviscous oil.

Example b' To an ether solution of 5.0 g. of isopropylZ-chlorosulfonylbenzoate, prepared as in Example 4, is added 5.0

g. of hexylarnine in ether solution. The resulting mixture is allowed tostand for 36 hours, then filtered. The mixture is concentrated in vacuo.The residue is isopropyl 2- (N-hexylsulfamoyl) -benzoate.

Example 6 An ethereal solution of 5.0 g. of dihexylamine is added to anether solution of 5 .0 g. of isopropyl 2-chlorosulfonylbenzoate,prepared as in Example 4. The resulting solution is allowed to stand atroom temperature for 36 hours. Working up as in Example 5 yieldsisopropyl 2(N,N-dihexylsulfamoyl) -benzoate.

1 Example 7 Example, 8

Ten grams of- 2-chlorosulfonylbenzoyl chloride, prepared as in Example3, is heated at C. with ml. of allyl alcohol for 4 hours. The excessallyl alcohol is removed in vacuo. The residue is dissolved in etherandtrated sulfuric acid and 200 ml. .of isobutyl alcohol is refluxed for 16hours. the filtrate is concentrated in vacuo. The residue is'taken up inethyl acetate, washed with 5% aqueous sodium bicarbonate solution andwith water. .The ethyl acetate solution is, dried over magnesiumsulfate, filtered" and concentrated in vacuo. The white solid residue.is recrystallized from aqueous methanol to give isobutyl2-sulfamoylbenzoate.

Example 3 A mixture of 50.0 g. of 2-sulfobenzoic anhydride and 100.0 g.of phosphorus pentachloride is refluxed for two hours. Low boilingmaterial is removed in vacuo, leaving as the residue crude2-chlorosulfony1benzoy1 chloride.

Five grams of this dichloride is heated in 50 m1. of isopropanol at 50C. for 2 hours. The excess alcohol is removed in vacuo. The residue,crude isopropyl Z-chloro- A mixture'of 10.0 g. of2-chlorosulfonylbenzoyl chloride, prepared as in Example 3, and 75 ml.of isopropanol is heated at 45 C. for 24 hours. The excess alcohol isremoved in vacuo. The residue, crude isopropyl 2-chlorosulfonylbenzoate,is dissolved inether and then added to The reaction mixture is'filtereidand added to 3.0 g. of ammonia in either. The resulting mix-. ture isallowed to stand at room temperature for 36 hours, filtered andconcentrated to give as the oily residue, allyl 2-sulfamoylbenzoate.

Example 9 A mixture of 5.0 g. of Z-chlorosulfonylbenzoyl chloride,prepared as in Example 3, and 25 ml. of propargyl alcohol is heated at50 C. for 4 hours.- The excess alcohol is removed in vacuo and theresidue is taken up in ether. This ethereal solution is added to 2.0 g.of ammonia in ether and the resulting solution is allowed to stand atroom temperature for 36 hours. Filtration and concentration of thefiltrate gives propargyl 2-sulfamoylbenzoate.

Example 10 j Example 11 A-mixture of 5.0 g. of 2 -chlorosulfonylbenzoylchlo' ride, prepared as in Example 3, and 50 ml. of S-hexen-l-ol isheated at 50 C. for 6 hours. The excess alcohol is removed in vacuo andthe residue is dissolved in ether and added to 50 ml. of an ethersolution saturated with ammonia. The resulting mixture is allowed tostand for 36 hours, then filtered. The filtrate is concentrated to giveas the residue S-hexenyl l-sulfarnoylbenzoate.

Example 12 Three grams of o-sulfobenzoic anhydride are dissolved in 15m1. of cyclobutanol by gentle warming. The solution is hQ lQQ at 40 C,for six' hours, then the excess cyclobutanol is removed in vacuo. Theresulting oily solid, cyciohutyl 2-sullobenzoate, is heated at refiuxwith 5.0 g. oi" phosphorus pentachloride for three hours. The phosphorusoxychloride which forms is removed in vacuo and the residue dissolved inether and washed with ice water. The ethereal solution of cyclobutyl2-chlorosulfonylbenzoate is treated with 5.0 g. of anhydrous ammonia.The resulting mixture is allowed to stand at room temperature for 24hours, then filtered. The filtrate is evaporated leaving an oil whichsolidifies on treatment with water. Recrystallization of this solidmaterial from aqueous isopropanol gives cyclobutyl 2-sulfamoylbenzoateas a white solid.

Example 13 A mixture of 3.0 g. of o-sulfobenzoic anhydride and ml. ofcyclopentanol is heated at 40 C. for six hours. The excess alcohol isremoved in vacuo to give, as the residue, cyclopentyl 2-sulfobenzoatewhich is then re- Example 14 Four grams of o-sulfobenzoic anhydride isheated with i 20 ml. of cyclohexanol at 40'for.six hours. The excesscyclohexanol is removed in vacuo to give, as the residue, cyclohexylZ-sulfobenzoate which is refluxed with 7.0 g. of phosphoruspentachloride for three hours. The phosphorus oxychloride which forms isremoved in vacuo.

The residue is dissolved in ether and Washed with ice A mixture of 35.0g. of saccharin, 20 drops of concentrated sulfuric acid and 200 ml. ofsec-butyl alcohol is refluxed for 16 hours. The reaction mixture isfiltered and concentrated in vacuo. The residue is dissolved in ethylacetate, washed with 5% aqueous sodium bicarbonateand with water. Dryingthe ethyl acetate solution over magnesium sulfate, filtering,concentrating in vacuo and recrystallizing the residue from aqueousmethanol gives secbutyl Z-sulfarnoylbenzoate.

Example 16 2 Five grams of o-sulfobenzoic anhydride are dissolved in 25m1. of t-butyl alcohol by gentle warming. Heating the solution at .45 C.for six hours and removing the excess t-butanol in vacuo gives, as theresidue, t-butyl 8 O aN in which R and R are members selected from thegroup consisting of hydrogen and lower alkyl and R is a member selectedfrom the group consisting of a branched alkyl group having from 3 to 6carbon atoms, a cycloalkyl group having from 4 m6 carbon atoms and anunsaturated acyclic 'hydrocarbon g'roup having from .3 to 6 carbonatoms. H

2. A chemical compound having the structural formula:

in which R is a branched alkyl group having from 3 to 6 carbon atoms.

3. Isopropyl 2-sulfamoylbenzoate.

4. Tertiary butyl 2-sulfamoylbenzoate.

5. Secondary butyl 2-sulfamoylbenzoate.

6. Allyl 2-sulfamoylbenzoate.

7. Proparg'yl 2-sulfamoylbenzoate.

References Cited in the file of this patent UNITED STATES PATENTSSeifert May 24, 1898 OTHER REFERENCES Beilstein: XI, 378 (1928).

1. A CHEMICAL COMPOUND HAVING THE STRUCTURAL FORMULA: